JP2842591B2 - Method for producing 4-hydroxycoumarin - Google Patents

Description

Description: TECHNICAL FIELD The present invention relates to a method for producing 4-hydroxycoumarin, which is useful as an intermediate material for pharmaceuticals, pesticides, particularly rodenticides and the like.

[Prior art] Conventionally, acetylsalicylic acid halide was used as a raw material for 4-
As a method for producing hydroxycoumarin, Czechoslovak Patent No. 153829 describes (1) reacting acetylsalicylic halide with acetoacetate in an aqueous solvent in the presence of an alkali to obtain α.
-Step of obtaining alkali salt of [2-hydroxybenzoyl] acetoacetate (2) Step of obtaining α- [2-hydroxybenzoyl] acetoacetate by salting out from the above reaction product solution (3) α- [2-hydroxy Benzoyl] acetoacetate is subjected to a cyclization reaction in the presence of sulfuric acid to obtain 4-hydroxycoumarin.
There is a statement that it can be obtained at 5.0%.

Also, in the examples of US Pat. No. 2,439,302, the desired product was obtained in a total yield of 53.4% by using the aqueous solvent in the above step (1) in substantially the same manner.

[Problems to be Solved by the Invention] However, since water is used as a main solvent when the acetylsalicylic acid halide is reacted with the acetoacetate in the step (1) in the conventional method, the reaction system is The slurry is highly slurryed or blocked to give a muddy state, making smooth stirring extremely difficult. In the step (2), the α- [2-hydroxybenzoyl] acetoacetate alkali salt obtained is poor in transitivity. The disadvantage is that it takes too long. In terms of the yield, the present inventors have found that when ethyl acetoacetate is used as a raw material, the yield from acetylsalicylic acid chloride is 76% (reference value 78.2%).
%), But when methyl acetoacetate is used, the yield from acetylsalicylic acid chloride is as low as 55% (Examples are not described in the literature). It becomes. Therefore, in the production of 4-hydroxycoumarin, the production and separation of the above-mentioned alkali salt of α- [2-hydroxybenzoyl] acetoacetate can be carried out smoothly, regardless of the type of the raw material acetoacetate ester. In any case, the problem is that the desired product can be obtained with a high yield, which is a problem to be solved for industrialization.

[Means for Solving the Problems] Accordingly, the present inventors have conducted intensive studies to solve the problems, and as a result, at the time of the reaction in the first step (1), a ketone solvent was used as a reaction solvent, In the step 2), the present inventors have found that the above object can be achieved when extracting as 3-acetyl-4-hydroxycoumarin easily soluble in a general organic solvent, and have completed the present invention.

That is, the present invention provides: (I) reacting acetylsalicylic halide with acetoacetate in a ketone solvent in the presence of an alkali to obtain α
-A step of obtaining an alkali salt of [2-hydroxybenzoyl] acetoacetic acid; (II) adding a mineral acid to the reaction product solution to cyclize the alkali salt of α- [2-hydroxybenzoyl] acetoacetic acid to give 3-acetyl; (III) deacetylation reaction of 3-acetyl-4-hydroxycoumarin in the presence of sulfuric acid to obtain 4-hydroxycoumarin. .

The feature of the present invention resides in that a ketone solvent is used as the reaction solvent (I) as described above. By using this ketone solvent, muddy or agglomeration of the system at the time of the reaction is prevented, stirring becomes easy, and in the subsequent step (II), the ketone solvent is used as it is as an extractant, so that the product is separated. This is extremely advantageous in terms of industrialization, for example, even if inexpensive methyl acetoacetate is used as a raw material, the desired product can be obtained with a good yield of 70 to 80%.

 Hereinafter, the method of the present invention will be sequentially described.

Step (I) The reaction of acetylsalicylic halide with acetoacetate in a ketone solvent in the presence of an alkali to give α- [2
-Hydroxybenzoyl] acetoacetic acid alkali salt is produced.

This step (I) is probably the reaction mechanism, and acetylsalicylic halide (i) and acetoacetate (ii)
First, alkyl α- [2-acetoxybenzoyl] acetoacetate is formed, and then the ester is hydrolyzed by an alkali to be converted to alkali α- [2-hydroxybenzoyl] acetoacetate (iii). I think that the.

In any case, the step (I) is a step of producing a compound (iii) by reacting the compounds (i) and (ii) in the presence of an alkali. Indicated by

As the acetylsalicylic acid halide, acetylsalicylic acid chloride and acetylsalicylic bromide can be used. The compound is used without solvent or dissolved in an inert organic solvent.

As the acetoacetate, various alkyl esters such as methyl acetoacetate, ethyl acetoacetate, propyl acetoacetate, and butyl acetoacetate can be used, and economically inexpensive methyl acetoacetate is advantageous.

The amount of acetoacetate used is 1 mol or more, preferably 1.2 to 1 mol, per 1 mol of acetylsalicylic acid halide.
2 mol is suitable.

As the alkali, sodium hydroxide and potassium hydroxide are economically advantageous. The alkali is added to the system as an aqueous solution, and the concentration of the alkali solution is suitably 20 to 50% by weight, preferably 40 to 50% by weight.

The amount of the alkali used cannot be clearly defined because it varies depending on the amount of acetylsalicylic acid halide. However, generally, 2 to 5 mol is suitable for 1 mol of acetoacetate ester.

The alkali may be charged in a necessary amount at the beginning of the reaction, but is preferably supplied to the system continuously or intermittently during the reaction of the compounds (i) and (ii).

As the ketone solvent, propanone, 2-butanone, 2
Any ketone such as -pentanone, 3-pentanone, 4-methyl-2-pentanone, 2-hexanone, cyclohexanone, 2-heptanone and 2-octanone can be used, and preferably a ketone having 4 to 8 carbon atoms is suitable. And
More preferably, 2-butanone, 4-methyl-2-pentanone, and cyclohexanone are practical. The amount of the ketone solvent to be used is 0.1 to acetylsalicylic acid halide.
5 times by weight or more, preferably 0.8 to 10 times by weight is appropriate.

In the present invention, the ketone solvent may be used alone or in a mixture with a small amount of another solvent such as water, as long as the effect is not hindered. In this case, it is necessary that the ketone solvent be contained in the entire reaction solvent in an amount of 10 to 85% by weight, preferably 20 to 70% by weight.

At the time of the reaction, an optional method such as adding an additional solvent during the reaction as necessary can be employed.

The reaction temperature is suitably 0 to 50 ° C, preferably 10 to 30 ° C. The reaction time is about 1 to 5 hours.

Step (II) Mineral acid is added to the above reaction product solution, and α- [2-hydroxybenzoyl] acetoacetic acid alkali salt is cyclized to give 3-acetyl-4-hydroxycoumarin.

The reaction formula is Indicated by

As the kind of the mineral acid to be used, hydrochloric acid, sulfuric acid, phosphoric acid, and the like can be used, and the mineral acid is added until the reaction product liquid has a pH of about 3 to 1. Extracting 3-acetyl-4-hydroxycoumarin from the acidic slurry liquid using an extractant,
After distilling off the extractant, crystalline 3-acetyl-4 containing an oily component was obtained.
-Obtain hydroxycoumarin. As the extractant to be used, ketone used for the reaction solvent is desirable, but a common organic solvent such as an ester such as toluene, benzene, and ethyl acetate can be used.

The obtained 3-acetyl-4-hydroxycoumarin is
It may be subjected to the next reaction as it is, but usually, it is washed with a lower alcohol having 1 to 4 carbon atoms, or is dissolved under reflux using the alcohol as a solvent, and after cooling to precipitate to remove impurities, etc. Provide for reaction.

Step (III) 3-acetyl-4-hydroxycoumarin is deacetylated in the presence of sulfuric acid to produce 4-hydroxycoumarin.

The reaction formula is Indicated by

In the deacetylation reaction, sulfuric acid having a concentration of 80 to 100% is used in the compound (iv) obtained in the step (II) in a 6 to 15-fold molar amount with respect to the compound (iv). Perform for about 8 hours. After completion of the reaction, the reaction solution is added to water, and the precipitate is removed to obtain 4-hydroxycoumarin.

4-Hydroxycoumarin can be obtained in an overall yield of 70-80% based on acetylsalicylic acid halide.

4-hydroxycoumarin obtained by the production method of the present invention is used as an intermediate material for pharmaceuticals, pesticides, especially rodenticides, etc.
It is an extremely useful compound in industry.

[Action] In the method of the present invention, in particular, the ketone solvent used in the step (I) is converted into a muddy reaction system during the reaction in the step (I),
It prevents agglomeration and improves the yield of 4-hydroxycoumarin when inexpensive methyl acetoacetate is used as a raw material.

[Examples and Comparative Examples] Hereinafter, the present invention will be described more specifically with reference to Examples and Comparative Examples.

Example 1 Step (I) A mixture of 104.4 g (0.9 mol) of methyl acetoacetate and 240 g of methyl isobutyl ketone (4-methyl-2-pentanone) was kept at 15 to 20 ° C. while stirring at a concentration of 40% by weight. Of sodium hydroxide aqueous solution at a constant rate over 2 hours. After 15 minutes from the start of the charging of the aqueous sodium hydroxide solution while maintaining the reaction solution temperature at 15 to 20 ° C., a solution prepared by dissolving 125 g (0.6 mol) of acetylsalicylic acid chloride in 60 g of methyl isobutyl ketone was added.
The reaction was performed at a constant rate over time. Subsequently, 600 g of methyl isobutyl ketone was added, and the mixture was stirred at a concentration of 40 g.
114.6 g (1.146 mol) of a weight% aqueous sodium hydroxide solution
Was continuously charged at a constant speed over 1 hour. At this time, the temperature of the reaction solution rose to 35 ° C. Stirring was continued for another 30 minutes.

Step (II) Add 263 g of concentrated hydrochloric acid to the above reaction mixture (PH1), and add
After stirring for 0 minutes, 470 g of water and 300 g of methyl isobutyl ketone were added, and the mixture was kept at 50 to 55 ° C. After the precipitate was dissolved, the organic layer was separated. The remaining water tank was further extracted with 250 g of methyl isobutyl ketone, and then combined with the organic layer under reduced pressure to obtain 152.5 g.
To yield crystals containing a brown oil.

The crystals were further dried at 45 ° C under reduced pressure of 1 mmHg for 16 hours,
g brown solid was obtained.

Step (III) To 477 g of sulfuric acid having a concentration of 97% by weight, 124.3 g of the solid was added with stirring, and the reaction temperature was maintained at 90 to 95 ° C. for 4 hours. After the completion of the reaction, the reaction solution was added to 2.4 kg of ice water, the precipitate was removed, and the obtained cake was sufficiently washed with water and dried. This result 7
4.9 g of a white to slightly yellow solid was obtained.

As a result of analysis by high performance liquid chromatography (HPLC), the purity of 4-hydroxycoumarin was 97%.

As a result of analysis by 'H-NMR and IR, it was found to be 4-hydroxycoumarin [mp = 213 ° C (decomposition)].

The yield of 4-hydroxycoumarin based on acetylsalicylic acid chloride was 74.7%.

Example 2 In Example 1, methyl acetoacetate was replaced with ethyl acetoacetate 117.
The same reaction was carried out except that 1 g and methyl isobutyl ketone were changed to methyl ethyl ketone (2-butanone).

4- to the acetylsalicylic acid chloride used
The yield of hydroxycoumarin was 72.6%.

Example 3 A reaction was carried out in the same manner as in Example 1 except for the following two points.

The brown oily crystals obtained in step (II)
1.8g Add 300g methanol and warm to 50 ℃, then 15-25 ℃
The mixture was cooled down and sucked. The obtained cake was further washed with a small amount of methanol to obtain 115.2 g of prismatic light brown crystals (containing 16.4% by weight of methanol). The crystals were used in Step (III) without drying.

Step (III) is the same as Example 1 (III) except that 115.2 g of the above-mentioned prismatic light brown crystals, 380 g of sulfuric acid having a concentration of 97% by weight, and 56 g of sodium hydrogen sulfate (monohydrate) were newly added at the time of preparation. The reaction was performed in the same manner as in the process.

4- to the acetylsalicylic acid chloride used
The yield of hydroxycoumarin was 74.4%.

Comparative Example 1 A reaction was carried out in the same manner as in Example 1 except that methyl isobutyl ketone was changed to toluene.

In the step (I), the system became muddy or clumpy, and stirring was difficult. As a result of continuing the reaction, the yield of 4-hydroxycoumarin based on acetylsalicylic acid chloride used was 51%.

Comparative Example 2 The reaction was carried out according to Czechoslovak Patent No. 153829.

Step (I) To a mixed solution of 83.8 g (0.645 mol) of ethyl acetoacetate and 108 g of ice water, 57 g (0.57 mol) of a 40% by weight aqueous sodium hydroxide solution was added while stirring at 0 to 5 ° C. 100 g (0.5 mol) of acetylsalicylic acid chloride was added to toluene 5
75 g of the solution (A) dissolved in 0 g was added at a constant rate over 30 minutes. Next, 28.0 g of 40% by weight aqueous sodium hydroxide solution
(0.28 mol) in 10 minutes, and then 3
7.5 g was added dropwise at a reaction temperature of 0 to 5 ° C over 20 minutes. Again at a reaction temperature of 0 to 5 ° C., 28.0 g of 40% by weight aqueous sodium hydroxide solution
Is added over 10 minutes, and 37.5 g of the solution (A) is added dropwise over 20 minutes. After further stirring at 0 to 5 ° C for 20 minutes, 95.5 g (0.955 mol) of a 40% by weight aqueous solution was added, and the mixture was stirred for 30 minutes. Next, 80 g of water was added and the mixture was stirred for 30 minutes.

(Up to this point, the reaction system became muddy or clumpy, and stirring was extremely difficult.) Further, 1 kg of water was added, and the mixture was heated to 80 ° C.

The following steps were performed in accordance with the steps (II) and (III) of Example 1.

As a result of analysis by high performance liquid chromatography (using an internal standard), the purity was 97%.

The yield of 4-hydroxycoumarin based on acetylsalicylic acid chloride was 76%.

Comparative Example 3 The reaction was carried out in the same manner as in Control Example 2 except that the solvent for dissolving acetylsalicylic acid chloride was changed from toluene to acetone.

In the same manner as in Comparative Example 2, in the step (I), the reaction system was muddy, and stirring was extremely difficult.

4- to the acetylsalicylic acid chloride used
The yield of hydroxycoumarin was 70%.

Control Example 4 In Control Example 3, ethyl acetoacetate was replaced with methyl acetoacetate 74.8.
The reaction was carried out in the same manner except that g was changed.

In the same manner as in Comparative Example 2, in the step (I), the reaction system was muddy, and stirring was extremely difficult.

4- to the acetylsalicylic acid chloride used
The yield of hydroxycoumarin was 53%.

[Effects] As described above, the production method of the present invention is particularly characterized in that a ketone solvent is used as a reaction solvent in the step (I), and when the ketone solvent is used in the reaction in the step (I), Unlike the conventional method, the reaction system is effective in preventing the reaction system from becoming muddy and agglomerated, facilitating stirring, and improving the yield when inexpensive methyl acetoacetate is used as a raw material.

────────────────────────────────────────────────── ─── Continuation of the front page (56) References JP-A-2-6481 (JP, A) US Patent 2439302 (US, A) Czechoslovak Patent 153829 (CZ) (58) Fields investigated (Int. . ^6, DB name) C07D 311/42 - 311/56 REGISTRY (STN ) CA (STN)

Claims (1)

(57) [Claims] (I) a step of reacting an acetylsalicylic halide with an acetoacetate ester in a ketone solvent in the presence of an alkali to obtain an alkali salt of α- [2-hydroxybenzoyl] acetoacetate; (II) the above reaction A step of adding a mineral acid to the resulting solution and cyclizing an alkali salt of α- [2-hydroxybenzoyl] acetoacetic acid to obtain 3-acetyl-4hydroxycoumarin; (III) 3-acetyl-4 in the presence of sulfuric acid A method for producing 4-hydroxycoumarin, which comprises a combination of steps of deacetylating hydroxycoumarin to obtain 4-hydroxycoumarin.